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Antistolling binnen de grenzen

Daalderop, J.H.H.

Publication date 2008

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Citation for published version (APA): Daalderop, J. H. H. (2008). Antistolling binnen de grenzen.

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Chapter1

Introduction and outline of the thesis

Anke van Geest-Daalderop

Thrombosis Service, Department of Laboratory of Clinical Chemistry and Haematology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands;

Departments of Clinical Chemistry and Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.

9 Chapter 1

Introduction

Discovery of the coumarin derivatives and vitamin K

The clinical use of coumarin derivatives as oral anticoagulant agents and the knowledge of the role of vitamin K were preceded by many years of scientific research which started after the observation of a haemorrhagic diathesis in cattle and chickens. Ultimately, serendipity plays an important role in the discovery of the coumarin derivatives. Around 1920 a long journey which led to the discovery, development, and application of the oral anticoagulants started in North Dakota, USA [1-3]. Karl P. Link describes this journey in his fascinating historical symposium [1]. The consumption of spoiled hay, made from sweet clover (Melilotus alba), by cattle, appeared to cause a severe hemorrhagic disease, often with lethal consequences. This disease was called 'sweet clover disease'. The clotting power of the blood diminished progressively and after withdrawal of the spoiled hay or transfusion of fresh blood, recovery of the coagulation abnormality was possible. In 1931 it was assumed that this disease was due to a lack of prothrombin, but the exact reason for the bleeding was still not known. Simultaneously, in 1933 Link et al started a study to develop a sweet clover plant to feed the cattle, without the substance 'coumarin' because coumarin smells sweet but tastes bitter. Coincidentally, in 1933 a desperate farmer came to his laboratory with a dead calf having bled without any clotting capacity. It would take another 6 years, until 1939, before Link and his staff members isolated the substance in the spoiled hay. Coumarins itself proved not to be pathogenic, but during spoilage an oxidative step of coumarin in the sweet clover appeared to lead to the formation of a 4-hydroxycoumarin, named dicumarol. In 1940 dicumarol was synthesized for the first time by the laboratory of Link at the University of Wisconsin. Between 1940-1942 dicumarol became available for clinical use as a prophylactic agent against thrombosis. From the start it was known that the dose had to be individualized to achieve optimal therapeutic effect and that several factors influenced this effect. In 1948 Link presented a coumarin derivate named Warfarin (Wisconsin Alumni Research Foundation with 'arin' from coumarin). Around 1950, searching in the USA and Europe for derivates of dicumarol that are more suitable as human therapeutic agents, Warfarin®, Warfarin sodium®, Tromexan® and Marcumar® were developed for clinical use. One coumarin

10 Introduction and outline of the thesis

derivative, a 'superwarfarin' with a very long half-life, was developed as a rat poison. The exact explanation of the mechanism of action of the 4- hydroxycoumarins was not known at that time. Another simultaneous development was the discovery of vitamin K by Henrik Dam [3,4] who investigated why chickens, when fed with a 'cholesterol- free' diet, were suffering from a haemorrhagic diathesis which caused an enormous impairment of the clotting of blood, apparently also by a deficiency of prothrombin. In 1935 Dam elucidated that this deficiency disease was caused by the lack of an antihaemorrhagic factor that he called 'vitamin K' (Koagulations- Vitamin in German and the Scandinavian languages). Edward A. Doisy elucidated the chemical nature of the vitamins K. In 1943 Dam and Doisy shared the Nobel Prize in Medicine for their discovery. The bleedings appeared to stop after consumption of some foods as alfalfa. But adding vitamin K in the laboratory to the plasma of bleeding chickens did nor correct the coagulation defect. Link had administered vitamin K to a bull with sweet clover disease which resulted in its recovery. Nevertheless the connection between the coumarin derivatives and vitamin K was not found at that time and the role of vitamin K as an antidote to dicumarol was not acknowledged by the clinicians for many years. It would take a long time, until about 1950, before vitamin K was recognized as an antidote for coumarin-related bleeding. After 1951, next to prothrombin new factors related to blood coagulation were found to be deficient due to lack of vitamin K: the procoagulant factors VII, IX and X, and the anticoagulant factors protein C and S. Alfred Loeliger described in 1963 that the factors II, VII, IX and X disappear in accordance with their different biological half-lives [5]. He also found that the activity of the four factors in long-term treatment, using the prothrombin time and a 2.5-fold prolongation, were equally depressed from 100% to approximately 20% in the long-acting phenprocoumon and similarly in acenocoumarol, warfarin sodium and dicoumarol. Around 1970 Johan Stenflo discovered in patients and cows, treated with dicoumarol, an 'abnormal' prothrombin that could not bind to Ca2+ [6,7]. The less normal prothrombin, the more abnormal prothrombin. He found the mechanism of action of vitamin K as a cofactor required to synthesize the biological active proteins by binding carboxyl groups to the glutamic acid residues of the vitamin K- dependent coagulation proteins. After activation of the coagulation system, these carboxyl groups enable the factors to bind to the phospholipid membranes serving as a catalytic surface for the formation of coagulation factor complexes, which is mediated by Ca2+.

11 Chapter 1

The next step was to identify the mechanism of action of vitamin K and the location where the vitamin K antagonists reduce the synthesis of the vitamin K- dependent proteins. In 1978 D. Whitlon et al described a model for normal vitamin K metabolism, the vitamin K-cycle, indicating how vitamin K is recycled many times, an effective way to use vitamin K [8]. One of the enzymes in this cycle is the vitamin epoxide reductase enzyme (VKOR) complex and the vitamin K antagonists inhibit this enzyme in the microsomes of the liver. This results in a blockade of the recycling process, a deficiency of vitamin K in the liver cell and consequently a depletion of the vitamin K-dependent clotting proteins.

Treatment with vitamin K antagonists

Coumarin derivatives act as antagonists of vitamin K and as a consequence inhibit the synthesis of vitamin K-dependent coagulation factors and act as oral anticoagulants. Worldwide they are one of the most frequently used drugs and are prescribed already more than 50 years. Vitamin K antagonists are effective for long-term primary or secondary prevention of venous and arterial thromboembolism, but unfortunately these agents increase the risk of bleedings. Treatment with vitamin K antagonists is complex because of its unpredictable effect, requiring frequent monitoring by determining the prothrombin time (PT), expressed as the International Normalized Ratio (INR). For each patient the appropriate dose has to be assessed repeatedly for the following reasons. Vitamin K antagonists have a narrow therapeutic range, the inter-individual dose response varies widely and the intra-individual response may vary depending on genetic factors and environmental influences as interaction with drugs, concomitant diseases and diet [9,10]. Also the therapy compliance of the patient and the competence of the physician who assesses the dose, determine the quality of treatment. The three most commonly used vitamin K antagonists are warfarin, used in many countries such as North America and the UK, acenocoumarol and phenprocoumon, mainly used in many European countries. These drugs have the same mechanism of action. The vitamin K antagonists are metabolized by various Cytochrome P isoenzymes, for instance CYP2C9 [11]. In recent years polymorphisms of the genotypes of both the VKOR-complex enzymes and the CYP 2C9 enzymes have been found. These polymorphisms influence the dose of the vitamin K antagonists and the stability of the treatment with these agents [11-14].

12 Introduction and outline of the thesis

The vitamin K antagonists have different half-lives. Acenocoumarol has a half-life of ± 11 hours, warfarin of ± 40 hours and phenprocoumon of ± 150 hours [15]. The vitamin K-dependent clotting factors also have different half-lives, factor VII ± 6, IX ± 20, X ± 40 and II ± 60 hours [9,16]. These different half-lives influence the effect of the vitamin K antagonists, especially in the first days after the initiation of the treatment, in case of under- or over-anticoagulation and when the treatment has to be interrupted temporarily. After initiation of the treatment, factor VII with its short half-life will rapidly decrease, resulting in an increasing INR after approximately two days. However, this anticoagulant effect may not produce an antithrombotic effect. Several studies demonstrated that the antithrombotic effect is caused in particular by the decrease of factor II [10,17]. Since factor II has a half-life of ± 60 hours, this effect may be seen after at least 5 days. For this reason, heparin treatment is necessary to overlap the delay of the antithrombotic effect, when this effect has to be achieved as soon as possible after the initiation of the treatment [18].

Vitamin K

Vitamin K is a fat-soluble trace element and green, leafy vegetables and certain vegetable oils are the main dietary source [19,20]. The current guideline for the vitamin K daily requirement for humans is about 100 μg/day. Vitamin K is a cofactor for the synthesis of vitamin K-dependent proteins such as coagulation proteins synthesized in the liver and non-coagulation proteins in other tissues such as bone (osteocalcin), cartilage and cardiovascular tissues (matrix Gla protein) [20,21]. Vitamin K is metabolized in the liver and has a half-life of about 60 hours. However, Knut-Olaf Haustein demonstrated that in the presence of the vitamin K antagonist phenprocoumon the elimination of vitamin K increased with a factor 2.6 [15]. Among others, the dietary intake of vitamin K determines the stability of the oral anticoagulant treatment and a poor dietary intake may cause less stability [22,23]. A low and steady supplementation of vitamin K to patients using vitamin K antagonists may prevent an instable treatment resulting in less INR values below and above the therapeutic target range and thus a decrease of the risk of thromboembolic events and bleeding complications [24,25,26]. In the management of the treatment with vitamin K antagonists, vitamin K may be administered in situations with excessive anticoagulation [27,28]. When

13 Chapter 1

the treatment has to be interrupted for invasive procedures, stopping for a few days in the case of vitamin K antagonists with a short half-life like warfarin and acenocoumarol is satisfactory to decrease the INR to the desired value, but for vitamin K antagonists with a long half-life such as phenprocoumon, administration of vitamin K is preferable to sole stopping of the drugs [10,29]. As vitamin K also plays a role in other tissues, a potential side-effect of treatment with vitamin K antagonists is the decreased action of vitamin K in these tissues which may result in bone loss and cardiovascular calcifications [21,30].

Prothrombin time/International Normalized Ratio

To adequately assess the dose of the vitamin K antagonist, a reliable result of the laboratory determination is required. Armand Quick is the father of the 'prothrombin time test' and this test, although modified, is still in use today [3,31]. In 1935 Quick stated that after the addition of a potent thromboplastin (he used rabbit brain) and a fixed quantity of calcium to oxalated plasma, the clotting time could be considered as a measure of the prothrombin concentration of the blood. The coagulation factors as factors V, VII and X, were unknown in those days. The result of the test was prolonged in rabbits with sweet clover disease and in vitamin K-deficient chickens, but also in patients treated with dicumarol or with liver disease. In the next years it appeared to be difficult to standardize the PT test mainly due to the variation in thromboplastins used, resulting in incomparable PT values and doses of vitamin K antagonists which may cause thromboembolic events or bleedings. Several proposals were done to improve the PT test, but it took a long time, until 1983, before the INR became the WHO international PT standardization scheme [32,33]. The INR is the PT ratioISI (the PT ratio to the power ISI, with the PT ratio equal to the patient PT divided by the mean normal PT and the ISI a shorthand notation for the International Sensitivity Index and used to calibrate the different thromboplastins). Although the use of the INR is a large improvement compared to the PT, an INR disagreement between different test systems still exists. Leon Poller, and in the Netherlands Alfred Loeliger and Antonius van den Besselaar made a large contribution to the development, calibration and standardization of PT/INR [33,34]. An external quality control program for systematic PT/INR testing is carried out by the independent reference laboratory RELAC (Reference Laboratory for Anticoagulant Control) founded by The

14 Introduction and outline of the thesis

Dutch Federation of Thrombosis Services, to ensure similar INR results between laboratories [35].

Therapeutic target ranges to prevent thromboembolic events and bleeding complications

To assess the optimal ranges of intensity for the various indications for the use of vitamin K antagonists, the so-called therapeutic target ranges, many clinical studies have been carried out, both in the past and still ongoing. The purpose of these studies is to find the ranges of INR values in which the treatment with vitamin K antagonists is effective to prevent thromboembolic events and at the same time safe to avoid bleeding complications. The optimal therapeutic target range is not the same for all clinical indications and for some indications the proper range is still a matter of debate. In 1979 a first proposal for optimal therapeutic anticoagulation was made by Loeliger [36] and in 1985 Loeliger et al reviewed the relevant literature for this subject [37]. In this study the ranges of INR values recommended were 1.5-2.5 for primary prevention of venous thrombosis, 2.5-4.0 for secondary prevention of venous thrombosis and for pre-, per- and postoperative prevention, 3.0-4.5 for patients 60 years of age and 3.5-5.0 for patients >60 years with active venous thrombosis and pulmonary embolism, prevention of arterial thromboembolism, artificial heart valves and arterial (coronary) thrombosis. The studies carried out thereafter, resulted in changes of these INR ranges. At present two therapeutic target ranges are in use. World-wide in the range of the lower intensity the INR value is between 2.0-3.0 and of the higher intensity between 2.5-3.5 [10]. To avoid in particular under-anticoagulation, the Dutch anticoagulation clinics apply slightly higher therapeutic target ranges, INR 2.5-3.5 and INR 3.0-4.0, respectively [38,39]. The lower therapeutic target range is effective for the indications atrial fibrillation [40,41], venous thromboembolism [42], cerebral ischemic events [43] and also prosthetic aortic valve of the new generation [44]. Several studies showed that the lowest intensity to be effective to prevent thromboembolic events for both atrial fibrillation and venous thromboembolism is an INR value of 2.0. Below this value, the under-anticoagulation causes inadequate protection against thromboembolic events [45-49]. The higher range is intended for the indications myocardial infarction in high-risk patients, prosthetic valves, in particular mitral valves, and some arterial

15 Chapter 1

vessel diseases [44,50-52]. The safety of treatment with vitamin K antagonists decreases when the INR value exceeds 4.0 because of the increasing risk of bleeding complications [53-56].

Assessment of the quality of treatment with vitamin K antagonists

Several methods have been described to assess the quality of treatment with vitamin K antagonists, such as the number of INR values within the therapeutic target ranges compared to the total number of INR values and the cross-section- of-the-files-technique [56,57]. The disadvantage of both methods is that they do not incorporate the time spent within, below or above the therapeutic target ranges. The method world-wide accepted nowadays is the linear interpolation method, developed by Frits Rosendaal et al in 1993 [58,59]. Applying this method the percentage time spent within, below and above the therapeutic target ranges is calculated. The U-shaped curve shows the relation of the incidence of thromboembolic events and bleedings at the various INR values. For large numbers of patients also cross-sectional calculations are still in use.

Management of treatment with vitamin K antagonists

In the management of the treatment with vitamin K antagonists in daily practice, many factors have to be taken into account in order to correctly assess and adjust the dose, such as the quality of INR determinations in the laboratory, the proper therapeutic target ranges, finding the appropriate dose in the initial phase of the treatment, the INR values outside the therapeutic target ranges, minor and major bleeding complications, the influence of environmental factors such as drug and food interactions, concomitant diseases, invasive procedures, and therapy compliance of the patient [10]. In the future, the possibility to determine variants of CYP2C9 and VKORC1 by genotyping may improve the assessment of the appropriate dose of the vitamin K antagonists [60,61]. It proves impossible to achieve all INR values to fall within the therapeutic target ranges. The quality of treatment with vitamin K antagonists increases when the management of this treatment is carried out by specialized anticoagulation

16 Introduction and outline of the thesis

clinics compared to routine medical care [62-65], by computerized dosing programs, by experienced physicians, and by dosing guidelines [66]. The first anticoagulation clinic, named 'Thrombosis Service', was established in 1949 in the city of Utrecht in the Netherlands by Frits L.J. Jordan [67]. By their scientific work and dedication to optimize this treatment, Jordan and also Loeliger provided high-quality treatment with vitamin K antagonists and both contributed to the development of the anticoagulation clinics. Nowadays, in the Netherlands the management of all outpatients with vitamin K antagonists is carried out by anticoagulation clinics, united in the Dutch Federation of Thrombosis Services. These clinics maximize high-quality treatment [38,39], having a computerized program for dosing calculations, protocols for dosing and education of patients, experienced physicians, so-called dosing assistants, well instructed personnel and the possibility to train and guide patients for self-management [68,69].

Outline of the thesis

This thesis presents several subjects with regard to the management of oral anticoagulant treatment with vitamin K antagonists carried out in the daily practice of anticoagulation clinics. Many factors influence the PT/INR value and therefore also the dose of the vitamin K antagonists to be taken by the individual patient. The results of the studies in this thesis intend to provide an insight in the effect of some of these factors and may contribute to an improvement of the assessment of the appropriate dose of the vitamin K antagonists. In Chapter 2, entitled "Omvang en kwaliteit van de antistollings- behandeling met cumarinederivaten door de Nederlandse Trombosediensten" ("Extent and quality of anticoagulation treatment with cumarin derivatives by the Dutch Thrombosis Services"), we performed a description of the data of 62 of the 63 Thrombosis Services in the Netherlands. These results were drawn from the medical annual reports over the period 1998-2002. The appropriate dose after initiation of the vitamin K antagonists is found often by trial and error. To predict the proper dose after the initiation of the cumarin derivative acenocoumarol, we developed a model, as described in Chapter 3, "Age and first INR after initiation of oral anticoagulant therapy with acenocoumarol predict the maintenance dosage". This model has been based on the age of the patient and the first INR after a standard initial dose of 6 mg

17 Chapter 1

acenocoumarol on the first day and 4 mg on the second day, or 6 mg, 4 mg and 2 mg on the first, second and third day, respectively. This model was prospectively evaluated in Chapter 4, "Improvement in the regulation of the cumarin derivative acenocoumarol after a standard initial dose regimen: prospective validation of a prescription model". The study of the influence of several pre-analytical factors on the PT/INR value is described in Chapter 5, "Preanalytical variables and off-site blood collection: Influences on the results of the prothrombin time/International Normalized Ratio test and implications for monitoring of oral anticoagulant therapy". We investigated the influence on the PT/INR value of the time between blood collection and PT/INR determination at several temperatures, mechanical agitation at several temperatures, time between centrifugation and PT/INR determination, and centrifugation at different times and with and without control of temperature. The time span between taking the dose of the short-acting acenocoumarol and the long-acting phenprocoumon and blood sample collection may influence the INR and the associated plasma levels of the coagulation factors. In Chapter 6, "The influence on INRs and coagulation factors of the time span between blood sample collection and intake of phenprocoumon or acenocoumarol: Consequences for the assessment of the dose", we studied the course of the INR values and coagulation factors during the day. Moreover we investigated whether any difference in INR values has consequences for the assessment of the proper dose of both vitamin K antagonists. Oral anticoagulation treatment with vitamin K antagonists often has to be interrupted when invasive procedures are planned. We carried out a study to find the appropriate method to interrupt this treatment in patients on acenocoumarol and phenprocoumon. This study is described in Chapter 7, "Invasive procedures in the outpatient setting: managing the short-acting acenocoumarol and the long- acting phenprocoumon".

18 Introduction and outline of the thesis

References

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19 Chapter 1

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20 Introduction and outline of the thesis

25. Rombouts EK, Rosendaal FR, van der Meer FJM. Daily vitamin K supplementation improves anticoagulant stability. J Thromb Haemost 2007;5:2043-2048. 26. Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007;109:2419-2423. 27. Penning-van Beest FJA, Rosendaal FR, Grobbee DE, van Meegen E, Stricker BHCh. Course of the International Normalized Ratio in response to oral vitamin

K1 in patients overanticoagulated with phenprocoumon. Br J Haematol 1999;104:241-245. 28. Dentali F, Ageno W. Management of coumarin-associated coagulopathy in the non-bleeding patient: a systematic review. Haematologica 2004;89:857-862. 29. Van Geest-Daalderop JHH, Hutten BA, Péquériaux NCV, de Vries- Goldschmeding J, Räkers E, Levi M. Invasive procedures in the outpatient setting: managing the short-acting acenocoumarol and the long-acting phenprocoumon. Thromb Haemost 2007;98:747-755. 30. Vermeer C, Hamulyák K. Vitamin K: lessons from the past. J Thromb Haemost 2004;2:2115-2117. 31. Dirckx JH. Armand J. Quick: pioneer and prophet of coagulation research. Ann Intern Med 1980;92:553-558. 32. Requirements for thromboplastins and plasma used to control oral anticoagulant therapy (Requirements for biological substances no. 30, revised 1982). In: WHO Expert Committee on Biological Standardization. Thirty-third report annex 3, WHO Technical Report Series, no 687. Geneva: World Health Organization, 1983. 33. Poller L. International Normalized Ratios (INR): 20 years. J Thromb Haemost 2004;2:849-860. 34. Van den Besselaar AMHP. Standardization of the prothrombin time in oral anticoagulant control. Haemostasis 1985;15:271-277. 35. Loeliger EA, van Dijk-Wierda CA, van den Besselaar AMHP, Broekmans AW, Roos J. Anticoagulant control and the risk of bleeding. In: Meade TW, ed. Anticoagulants and myocardial infarction: a reappraisal. John Wiley & Sons Ltd, 1984:135-177. 36. Loeliger EA. The optimal therapeutic range in oral anticoagulation. History and proposal. Thromb Haemostasis 1979;42:1141-1152. 37. Loeliger EA, Broekmans AW. Optimal therapeutic anticoagulation. Haemostasis 1985;15:283-292.

21 Chapter 1

38. Van Geest-Daalderop JHH, Sturk A, Levi M, Adriaansen HJ. Extent and quality of anticoagulation treatment with coumarin derivatives by the Dutch Thrombosis Services. Ned Tijdschr Geneesk 2004;148:730-735. Dutch. 39. Gadisseur APA, van der Meer FJM, Adriaansen HJ, Fihn SD, Rosendaal FR. Therapeutic quality control of oral anticoagulant therapy comparing the short- acting acenocoumarol and the long-acting phenprocoumon. Br J Haematol 2002;117:940-946. 40. Atrial fibrillation investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized control trials. Arch Intern Med 1994;154:1449-1457. 41. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;119:429S-456S. 42. Büller HR, Agnelli A, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;119:401S-428S. 43. The stroke prevention in reversible ischemia trial (SPIRIT) study group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997;42:857-865. 44. Vink R, Van den Brink RB, Levi M. Management of anticoagulant therapy for patients with prosthetic heart valves or atrial fibrillation. Hematology 2004;9:1- 9. 45. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-1026. 46. Hull RD, Hirsh J, Jay R, Carter C, England C, Gent M, Turpie AGG, McLoughlin D, Dodd P, Thomas M, Raskob G, Ockelford P. Different intensities of oral anticoagulant therapy in the treatment of proximal vein thrombosis. N Engl J Med 1982;307:1676-1681. 47. Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, MacKinnon B, Weitz, JI, Crowther MA, Dolan S, Turpie AG, Geerts W, Solymoss S, van Nguyen P, Demers C, Kahn SR, Kassis J, Rodger M, Hambleton J, Gent M. Extended low-intensity anticoagulation for thromboembolism investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-639.

22 Introduction and outline of the thesis

48. Kovacs J. The standard is still the standard or why an INR of 2-3 is still the optimal intensity for secondary prevention of venous thromboembolism. J Thromb Thrombolysis 2006;21:53-56. 49. Veeger NJGM, Piersma-Wichers M, Tijssen JGP, Hillige HL, van der Meer J. Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol 2005;128:513-519. 50. Cannegieter SC, Rosendaal FR, Wintzn AR van der Meer FJM, Vandenbroucke JP, Briët E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995;333:11-17. 51. Azar AJ, Cannegieter SC, Deckers JW, Briët E, van Bergen PF, Jonker JJ, Rosendaal FR. Optimal intensity of oral anticoagulant therapy after myocardial infarction. J Am Coll Cardiol 1996;27:1349-1355. 52. Tangelder MJD, Algra A, Lawson JA, Hennekes S, Eikelboom BC. Optimal oral anticoagulant intensity to prevent secondary ischemic and hemorrhagic events in patients after inguinal bypass graft surgery. Dutch BOA Study Group. J Vasc Surg 2001;33:522-527. 53. Fitzmaurice DA, Blann AD, Lip GYH. Bleeding risks of antitrombotic therapy. Clinical review. BMJ 2002;325:828-831. 54. Van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993;153:1557-1562. 55. Palareti G, Leali N, Cocheri S, Poggi M, Manotti C, D’angelo A, et al Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996;348:423-428. 56. Loeliger EA. Laboratory control, optimal therapeutic ranges and therapeutic quality control in oral anticoagulation. Acta Haematol 1985;74:125-131. 57. Van den Besselaar AMHP, van der Meer FJM, Gerrits-Drabbe CW. Therapeutic control of oral anticoagulant treatment in the Netherlands. Am J Clin Pathol 1988;90:685-690. 58. Rosendaal FR, Cannegieter SC, van der Meer FJM, Briet E. A method to determine the optimal intensity of oral anticoagulation therapy. Thromb Haemost 1993;39:236-239. 59. Hutten BA, Prins MH, Redekop WK, Tijssen JGP, Heisterkamp, S, Büller HR. Comparison of three methods to assess therapeutic quality control of treatment with vitamin K antagonists. Thromb Haemost 1999;82:1260-1263.

23 Chapter 1

60. Sconce EA, Kahn TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329-2333. 61. Oldenburg J, Bevans CG, Fregin A, Geisen C, Müller-Reible, Watzka M. Current pharmacogenetic developments in oral anticoaglation therapy: the influence of variant VKORC1 and CYP2C9 alleles. Thromb Haemost 2007;98:570-578. 62. Pengo V, Pegoraro C, Cucchini U, Iliceto S. Worldwide management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis 2006;21:73- 77. 63. Ansell J, Hollowell J, Pengo V, Martinez-Brotons F, Caro J. Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management (ISAM). J Thromb Thrombolysis 2007;23:83-91. 64. Kristofferson AH, Thue G, Sandberg S. Postanalytical external quality assessment of warfarin monitoring in primary healthcare. Clin Chem 2006;52:1871-1878. 65. Wilson SJ, Wells PS, Kovacs MJ, Lewis GM, Martin J, Burton E, Anderson DR. Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial. CMAJ. 2003;169:293-298. 66. Van den Bemt, PMLA, Joosten P, Risselada A, van den Boogaart MHA, Egberts ACG, Brouwers JRBJ. Stabilization of oral anticoagulant therapy in hospitalized patients and characteristics associated with lack of stabilization. Pharm World Sci 2000;22:147-151. 67. Loeliger EA. In de greep van de protrombinetijd. Leiden 1985, Brill EJ, ed. Dutch. 68. Cromheecke ME, Levi M, Colly LP, de Mol BJ, Prins MH, Hutten BA, Mak R, Keyzers KC, Büller HR. Oral anticoagulation self-management and management by a specialist anticoagulation clinic: a randomised cross-over comparison. Lancet 2000;356:97-102. 69. Gadisseur APA, Breukink-Engbers WGM, van der Meer FJM, van den Besselaar AMHP, Sturk A, Rosendaal FR. Comparison of the quality of oral anticoagulant therapy through patient self-management and management by specialized anticoagulation clinics the Netherlands. Arch Intern Med 2003;163:2639-2646.

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